Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a small molecule drug that has been used for many years in Japan and Korea for the treatment of bronchial asthma as well as for treatment of cerebrovascular disorders such as post-stroke dizziness. It is sold in these countries under the tradename, Ketas®. Marketed indications for ibudilast in Japan include its use as a vasodilator, for treating allergy, eye tissue regeneration, ocular disease, and treatment of allergic ophthalmic disease (Thompson Current Drug Reports). Its use in the treatment of both chronic brain infarction (ClinicalTrials.gov) and multiple sclerosis (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005) is currently being explored in separate, ongoing clinical trials.
The mechanisms of action of ibudilast have been widely explored. Its role as a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) has been described (Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Additionally, ibudilast has been reported to act as an LTD4 antagonist, an anti-inflammatory, a PAF antagonist, and a vasodilatatory agent (Thompson Current Drug Reports). Ibudilast is also thought to exert a neuroprotective role in the central nervous system of mammals, presumably via suppression of the activation of glial cells (Mizuno et al. (2004) Neuropharmacology 46: 404-411). New uses for ibudilast continue to be explored.
An analog of ibudilast, KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo(1,5-a)pyridine, developed by Kyorin Pharmaceutical Co., has been reported to possess antiplatelet and antithrombotic activity (Momo, K., et al., Arzneimittelforschung, 1992, January 42(1), 32-9). KC-764 possesses a chemical structure that differs from ibudilast in the substituents at the 2- and 3-ring positions. Interestingly, its reported therapeutic use, primarily as an antiplatelet agent, differs significantly from that of the parent compound, ibudilast.
The applicants have surprisingly discovered that certain compounds belonging to the substituted pyrazolo[1,5-a]pyridine family are useful in the treatment of conditions such as neuropathic pain. Additionally, such compounds are useful for treating one or more of the following: inflammatory conditions, opiate withdrawal and taxol-induced neuropathy, as well as for antiviral therapy, among others. The shortcomings of current therapeutic approaches in each of these areas are well-known. It is believed that the compounds described herein provide one or more advantages over currently existing therapies.